Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

Abstract

Lee JH, Gao Z, Ye J. Regulation of 11␤-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-B and HIF-1␣. Am J Physiol Endocrinol Metab 304: E1035-E1041, 2013. First published March 19, 2013; doi:10.1152/ajpendo.00029.2013.-11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) is involved in the pathogenesis of type 2 diabetes by generating active glucocorticoids (cortisol and corticosterone) that are strong inhibitors of angiogenesis. However, the mechanism of 11␤-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11␤-HSD1 expression in visceral and subcutaneous adipose tissue (AT) of diet-induced obese (DIO) mice during weight gain and investigated the gene regulation by hypoxia in vitro. 11␤-HSD1 mRNA was reduced in the adipose tissues during weight gain in DIO mice, and the reduction was associated with an elevated expression of angiogenic factors. In vitro, 11␤-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-B (NF-B) enhanced but the hypoxia inducible factor-1␣ (HIF-1␣) reduced 11␤-HSD1 expression. 11␤-HSD1 expression was elevated by NF-B in epididymal fat of aP2-p65 mice. The hypoxia-induced 11␤-HSD1 expression was attenuated by NF-B inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1␣-null cells. These data suggest that 11␤-HSD1 expression is upregulated by NF-B and downregulated by HIF-1␣. During AT expansion in DIO mice, the reduction of 11␤-HSD1 expression may reflect a dominant HIF-1␣ activity in the adipose tissue. This study suggests that NF-B may mediate the inflammatory cytokine signal to upregulate 11␤-HSD1 expression.11␤-hydroxysteroid dehydrogenase type 1; nuclear factor-B; hypoxiainducible factor-1␣; hypoxia; hyperinsulinemia; angiogenesis; inflammation; obesity; type 2 diabetes 11␤-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11␤-HSD1) that converts inactive glucocorticoids (GCs; cortisone and 11-dehydrocorticosterone) into active GCs (cortisol and corticosterone) plays a role in the pathogenesis of insulin resistance. Global inactivation of 11␤-HSD1 by gene knockout prevents insulin resistance and reduces hepatic gluconeogenesis in obese mice (21). 11␤-HSD1 overexpression in adipose tissue (AT) generates visceral obesity and systemic insulin resistance in transgenic mice (23). Liver-specific overexpression of 11␤-HSD1 leads to insulin resistance in the absence of obesity in mice (31). Conversely, global inactivation of the 11␤-HSD1 gene protects mice from diet-induced obesity (21,25,26). 11␤-HSD1 has been a drug target in the study of insulin resistance, and its inhibition using a pharmacological approach improves insulin sensitivity in diabetic mice (2). 11␤-HSD1 is expressed in many cell types, including adipocytes, and the expression is increased during adipocyte differentiation (7). 11␤-HSD1 elevation in adipocytes is proposed to be a common molecular etiology for visceral obe...

The expression of epidermal growth factor-like domain 7 regulated by oxygen tension via hypoxia inducible factor (HIF)-1α activity

“…Epidermal growth factor-like domain-7 (Egfl7) is an endothelial cell-derived secreted factor and is necessary for vascular formation [5,6]. The expression of Egfl7 is strongly upregulated in many proliferative tissues, including tumors and reproductive organs during pregnancy or inflammation [5], and is detected in atherosclerotic plaques and in the regenerating arterial endothelium with a balloon-expandable injury [7,8].…”

Association between Plasma Cellular Hypoxia and Mitochondrial Dysfunction Biomarkers and Disease Risk and Prognostic Factors in Type 2 Diabetic Saudi Patients

“…Inactivation of HIF-1α reduces metabolic phenotype, promotes adipocyte browning and induces mitochondrial biogenesis and function in visceral adipocytes, culminating to protection from obesity and IR (29,30). Synthesis of the anti-insulin, anti-angiogenic glucocorticoids is downregulated by HIF-1α (31). The significant reduction in HIF-1α levels in the current sample of patients was pathogenetic since induction of HIF-1α is a protective factor for β-cells against apoptosis (32).…”

HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs

“…NF-κB was reported to positively regulate HSD11B1 expression in human synovial fibroblasts and human dermal fibroblasts 31 and in adipocytes of diet-induced obese mice 32 . However, it was also shown to inhibit the expression of HSD11B1 in mouse skeletal muscle cells 33 .…”